Methods and apparatus for aerosolizing a substance

ABSTRACT

A device for aerosolizing a liquid includes a chamber having a deformable wall which expands and contracts as fluid is delivered and expelled from a fluid chamber. The chamber is partially bounded by a vibrating structure having holes therein for expelling the fluid. In another aspect, the invention provides exemplary aerosolization apparatus and methods for aerosolizing a substance. A liquid is transferred from a first chamber into a second chamber having a substance that is in a dry state to form a solution. The solution is then transferred from the second chamber and onto an atomization member. The atomization member is operated to aerosolize the solution.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.09/483,096, filed Jan. 14, 2000, now U.S. Pat. No. 6,427,682, which is acontinuation in part application of U.S. patent application Ser. No.09/313,914, filed May 18, 1999, now pending which is a continuation inpart of Ser. No. 09/149,426, filed Sep. 8, 1998 now U.S. Pat. No.6,205,999, which is a continuation in part of Ser. No. 09/095,737, filedJun. 11, 1998 now U.S. Pat. No. 6,014,970, which is a continuation inpart of Ser. No. 08/417,311, filed Apr. 5, 1995 now U.S. Pat. No.5,938,117, the complete disclosures of which are herein incorporated byreference.

BACKGROUND OF THE INVENTION

The invention relates generally to the field of inhalation drug therapy,and in particular to the inhalation of aerosolized chemical substances.In one aspect, the invention provides a portable inhaler having acartridge for storing a chemical substance in a dry state and a liquiddispenser to introduce a liquid to the substance to form a solution.Immediately after formation of the solution, the inhaler aerosolizes thesolution so that it may be administered to a patient.

The atomization of liquid medicaments is becoming a promising way toeffectively deliver many medicaments to a patient. In particular thereis a potential for pulmonary delivery of protein peptides and otherbiological entities. Many of these are easily degraded and becomeinactive if kept in a liquid form. Proteins and peptides often exhibitgreater stability in the solid state. This results primarily from twofactors. First, the concentration of water, a reactant in severalprotein degradation pathways, is reduced. See Stability of ProteinPhannaceuticals, M. C. Manning, K. Patel, and R. T. Borchardt, Pharm.Res. 6, 903-918 (1989), the complete disclosure of which is hereinincorporated by reference. Second, the proteins and other excipients areimmobilized in the solid state. Water is a reactant in hydrolysisreactions, including peptide change and cleavage, and deamidation.Reducing the water concentration by freeze-drying or spray drying,reduces this reactant concentration and therefore the rates of thesedegradation pathways.

The mobility of the peptides or proteins, as well as other molecules inthe formulation, are reduced in the solid or dry state. See MolecularMobility of Amorphous Pharmaceutical Solids Below Their Glass TransitionTemperatures, B. C. Hancock, S. L. Shamblin, and G. Zografi, Pharm. Res.12, 799-806 (1995), the complete disclosure of which is hereinincorporated by reference. For the peptides or proteins, this reducesthe rate of intermolecular interactions as well as intramolecularconformational changes or fluctuations in conformation. Minimization ofintermolecular interactions will reduce protein and peptideaggregation/precipitation, and will also reduce the rate of diffusion ofchemical reactants to the protein or peptide which will slow the rate ofchemical degradation pathways. Reduction in intramolecularconformational changes reduces the rate at which potentially reactivegroups become available for chemical or intermolecular interaction. Therate of this reaction may decrease as the water concentration, andmobility of the protein, is reduced.

One way to produce protein in solid or dry state is to transform theliquid into a fine powder. When used for inhalation delivery, suchpowders should be composed of small particles with a mean mass diameterof 1 to 5 microns, with a tight particle size distribution. However,this requirement increases the processing and packaging cost of the drypowder. See also U.S. Pat. No. 5,654,007 entitled “Methods and Systemfor Processing Dispersible Fine Powders” and U.S. Pat. No. 5,458,135entitled “Methods and Devices for Delivering Aerosolized Medicaments”,the disclosures of which are incorporated herein by reference.

An easier way to transform a liquid solution to solid or dry form is touse a freeze drying process where a liquid solution is converted to asolid substance that can be readily reconstituted to a liquid solutionby dissolving it with a liquid, such as water. Hence, one object of thepresent invention is to provide a way to store a solid substance andcombine the solid substance the with a liquid to form a solution. Oncethe solution is formed, it is another object of the invention to rapidlytransport the solution to an atomization device to allow the solution tobe aerosolized for administration. In this way, the solution isaerosolized immediately after its reconstitution so that the degradationrate of the substance is reduced.

A variety of nebulization devices are available for atomizing liquidsolutions. For example, one exemplary atomization apparatus is describedin U.S. Pat. No. 5,164,740, issued to Ivri (“the '740 patent”), thecomplete disclosure of which is herein incorporated by reference. The'740 patent describes an apparatus which comprises an ultrasonictransducer and an aperture plate attached to the transducer. Theaperture plate includes tapered apertures which are employed to producesmall liquid droplets. The transducer vibrates the plate at relativelyhigh frequencies so that when the liquid is placed in contact with therear surface of the aperture plate and the plate is vibrated, liquiddroplets will be ejected through the apertures. The apparatus describedin the '740 patent has been instrumental in producing small liquiddroplets without the need for placing a fluidic chamber in contact withthe aperture plate, as in previously proposed designs. Instead, smallvolumes of liquid can be placed on the rear surface of the apertureplate and held to the rear surface by surface tension forces.

A modification of the '740 apparatus is described in U.S. Pat. Nos.5,586,550 (“the '550 patent”) and 5,758,637 (“the '637 patent”), thecomplete disclosures of which are herein incorporated by reference.These two references describe a liquid droplet generator which isparticularly useful in producing a high flow of droplets in a narrowsize distribution. As described in the '550 patent, the use of anon-planar aperture plate is advantageous in allowing more of theapertures to eject liquid droplets. Furthermore, the liquid droplets maybe formed within the range from about 1 μm to about 5 μm so that theapparatus will be useful for delivering drugs to the lungs.

Hence, it is a further objective of the invention to provide devices andmethods to facilitate the transfer of liquid solutions (preferably thosewhich have just been reconstituted) to such aerosolizing apparatus sothat the solution may be atomized for inhalation. In so doing, oneimportant consideration that should be addressed is the delivery of theproper dosage. Hence, it is still another object of the invention toensure that the proper amount of liquid medicament is transferred to anaerosol generator so that a proper dosage may be delivered to the lungs.

In still another aspect of the present invention, the present inventionis directed to methods and devices for delivering fluids to a vibratingelement

SUMMARY OF THE INVENTION

The invention provides exemplary systems, apparatus and methods forreconstituting a solid phase substance, e.g., a substance that is in adry state, with liquid to form a solution and for transporting thesolution to an aerosol generator for subsequent atomization. In oneexemplary embodiment, the system comprises a liquid dispenser, acartridge containing a substance in a dry state, and an aerosolgenerator. In use, the cartridge is coupled to an outlet of thedispenser and the dispenser is operated to dispense liquid from theoutlet and into the cartridge. The liquid then flows through thesubstance and exits the cartridge as a solution.

In an exemplary aspect, the cartridge is replaced and disposed aftereach use. After removal of the cartridge the user may optionally operatethe liquid dispenser to deliver liquid to the aerosol generator for asubsequent cleaning cycle. In another exemplary aspect, a liquid outletof the cartridge is positioned near the aerosol generator such that thesolution is dispensed onto the aerosol generator and is readilyavailable for atomization.

The Liquid Dispenser

In an exemplary embodiment, the liquid dispenser comprises a mechanicalpump that is attached to a canister. The liquid dispenser is disposedwithin a housing of the inhaler and is configured to deliver apredetermined volume of liquid each time the mechanical pump isoperated. The dispensed liquid then flows directly from the pump to thecartridge to form a solution which in turn is deposited on the aerosolgenerator.

In one particular aspect, the liquid is a saline solution or sterilewater and may optionally contain an anti-microbial additive. Aspreviously mentioned, the solid substance in the cartridge preferablycomprises a chemical that is in the dry state which is reconstitutedinto a solution upon introduction of the liquid from the liquiddispenser.

In one particularly preferable aspect, the mechanical pump comprises apiston pump that is connected to the canister. The piston pump comprisesa spring-loaded piston member that is slidable within a cylindricalmember which defines a metering chamber. When the piston member is movedto a filling position, the metering chamber is filled with liquid fromthe canister. When released, the piston member moves to a dispensingposition to dispense a known volume of liquid from the metering chamber.In this way, each time the pump is operated, a unit volume of liquid isdispensed from the piston pump.

In one particularly preferable aspect, movement of the piston membertoward the filling position creates a vacuum inside the cylindricalmember that gradually increases until the piston member reaches a pointwhere a passage is provided between the piston member and thecylindrical member. At this point, the piston member has reached thefilling position to allow liquid from the canister to be drawn by thevacuum into the metering chamber of the cylinder. At this point, thepiston member is released and returns by the force of the spring back tothe dispensing position. During the return travel of the piston memberto the dispensing position, the liquid in the metering chamber isdisplaced through an outlet of the pump.

In another particular aspect, the piston pump is configured to delivervolumes of liquid in the range of about 10 μL to about 50 μL each timethe pump is operated. In another aspect, the piston pump is configuredsuch that it will dispense a full unit volume only if the user fullydepresses the piston to the filling position. If the piston member isonly partially depressed, no liquid will be dispensed. In this manner,partial dosing is prevented.

In still yet another aspect, the liquid dispenser further includes avalve which serves to eliminate the dead volume in the piston pump,thereby inhibiting microbial inflow into the liquid dispenser. The valvepreferably comprises a tubular valve seat that is slidably disposedabout a distal end of the piston member. In this way, the liquid withinthe metering chamber moves the tubular valve seat distally over thepiston member to allow the liquid in the metering chamber to bedispensed by flowing between the piston member and the tubular valveseat when the piston member is moved toward the dispensing position. Thetubular valve seat is also slidable within the cylindrical member, andthe cylindrical member defines a stop to stop distal movement of thetubular valve seat relative to the piston member after the unit volumeof liquid has been dispensed from the metering chamber. Further, whenthe spring forces the distal end of the piston member into a distal endof the tubular valve seat, a seal is provided between the piston memberand the tubular valve seat to prevent microbial inflow into the pistonpump. Hence, use of the tubular valve seat in combination with thepiston member and the cylindrical member allows for a unit volume of theliquid within the piston pump to be dispensed and further provides aseal to prevent microbial inflow into the piston pump.

The Drug Cartridge

The cartridge of the invention allows for the storage of a chemical in adry state. When a liquid is introduced into the cartridge, the chemicalsubstance dissolves within the liquid to form a solution just prior toaerosolization of the solution.

In one exemplary embodiment, the cartridge comprises a housing having aninlet opening and an outlet opening. Disposed in the housing is achemical substance which is in a dry state. As liquid flows through thehousing, the substance dissolves and flows through the outlet opening asa solution. The chemical substance may be any one of a variety ofchemical substances, such as proteins, peptides, small molecule chemicalentities, genetic materials, and other macromolecules and smallmolecules used as pharmaceuticals. One particular substance is alyophilized protein, such as interferon alpha or alpha 1 prolastin. Thelyophilized substance is preferably held in a support structure toincrease the surface area that is in contact with the liquid, therebyincreasing the rate by which the substance is dissolved. The supportstructure is preferably configured to hold the lyophilized substance ina three-dimensional matrix so that the surface area of the substancethat is contact with the liquid is increased. Exemplary types of supportstructures include open cell porous materials having many tortuous flowpaths which enhance mixing so that the solution exiting from the outletend is homogenized. Alternatively, the support structure may beconstructed of a woven synthetic material, a metal screen, a stack ofsolid glass or plastic beads, and the like.

When used in connection with the aerosolizing apparatus of theinvention, actuation of the liquid dispenser introduces liquid into theinlet opening, through the support structure to dissolve the substance,and out the outlet opening where it is disposed on the aerosol generatoras a solution. The aerosol generator is then operated to aerosolize thesolution. In this way, the substance is stored in a solid state untilready for use. As previously described, the flow of liquid from theliquid dispenser is produced during the return stroke of the pistonmember, i.e. as the piston member travels to the dispensing position.Since the return stroke is controlled by the spring, it is not dependenton the user. In this way, the flow rate is the same each time the liquiddispenser is operated, thereby providing a way to consistently andrepeatedly reconstitute the solution.

In one particular aspect, the cartridge includes a coupling mechanism atthe inlet opening to couple the cartridge to the liquid dispenser. Inthis way, the cartridge is configured to be removable from the liquiddispenser so that it may be removed following each use and discarded. Instill another aspect, the cartridge is filled with the chemicalsubstance while in a liquid state. The substance is then freeze driedand converted to a solid state while in the cartridge.

The Aerosol Generator

In an exemplary embodiment, the aerosol generator that is employed toaerosolize the solution from the cartridge is constructed in a mannersimilar to that described in U.S. Pat. Nos. 5,586,550 and 5,758,637,previously incorporated herein by reference. In brief, the aerosolgenerator comprises a vibratable member having a front surface, a rearsurface, and a plurality of apertures which extend between the twosurfaces. The apertures are preferably tapered as described in U.S. Pat.No. 5,164,740, previously incorporated herein by reference. In oneparticular aspect, the vibratable member is preferably hemispherical inshape, with the tapered apertures extending from the concave surface tothe convex surface. In use, the solution from the cartridge is suppliedto the rear surface of the vibratable member having the large opening.As the vibratable member is vibrated, the apertures emit the solutionfrom the small openings on the front surface as an aerosolized spray.The user then simply inhales the aerosolized spray to supply thechemical to the patient's lungs.

Alternative Embodiments

The invention further provides exemplary methods and apparatus foraerosolizing a solution. In one exemplary embodiment, an apparatuscomprises a cartridge having a first chamber, a second chamber, and amoveable divider between the first and the second chambers. An exitopening is included in the cartridge and is in communication with thesecond chamber. A liquid is disposed in the first chamber, and asubstance that is in a dry state is in the second chamber. The apparatusfurther includes a piston that is translatable within the cartridge totransfer the liquid from the first chamber and into the second chamberto form a solution. An aerosol generator is further provided and isdisposed near the exit opening to receive the solution from thecartridge and produce an aerosolized solution. In this way, thesubstance may be maintained in a dry state as with other embodimentsuntil ready for aerosolization. To form the solution, the piston ismoved within the cartridge to force the liquid from the first chamberand into the second chamber. Further translation of the piston forcesthe recently formed solution from the second chamber and onto theaerosol generator where the solution is aerosolized.

In one particular aspect, the divider has a home position where a sealis formed between the divider and the cartridge. In this way, the liquidmay be held in the first chamber until the piston is translated.Preferably, the cartridge includes at least one groove that is disposedat least part way between the first and second chambers. In this way, asthe piston is moved within the first chamber, the liquid (which isgenerally incompressible) moves the divider toward the second chamber toallow the liquid to pass around the divider and into the second chamber.The groove preferably terminates at the second chamber so that when thepiston moves the divider into the second chamber, a seal is formedbetween the cartridge and the divider to force the solution from thesecond chamber and out the exit opening.

In some cases, it may be desirable to draw the solution back into thefirst chamber to facilitate mixing. This can be accomplished bywithdrawing the piston back through the first chamber to create a vacuumin the first chamber. To dispense the solution, the piston is translatedback through the first and second chambers as previously described.

In one particular aspect, a filter is disposed across the exit openingto prevent larger particles from exiting the chamber and clogging theaerosol generator. In another aspect, the apparatus includes a motor totranslate the piston. In this way, an aerosolized solution may besupplied to the patient simply by actuating the motor.

In yet another aspect of the present invention, the present invention isalso directed to a device for aerosolizing a liquid having a chamberwith a deformable wall. The wall moves between collapsed and expandedpositions to accommodate varying volumes of fluid. The chamber moves tothe expanded position in response to fluid being delivered to thechamber and collapses as fluid is expelled. The chamber contains avolume of 10-1000 μL, more preferably 10-750 μL, and most preferably10-500 μL, while preferably maintaining the fluid pressure of less than15 psi in the chamber. A container, which holds enough liquid to fillthe chamber at least three times, delivers fluid to the chamber. Thewall may be attached to the vibrating structure or may be replaced withthe container.

The device preferably has a valve positioned between the container andthe chamber to isolate the chamber from the container. The valve may beformed with the wall so that the valve forms part of the wall. The valveis preferably positioned less than 1 mm from the back side of thevibrating structure so that the chamber has a low volume when collapsed.The chamber preferably has a volume of less than 5 μL and morepreferably less than 2 μL when collapsed. The valve is preferablypositioned adjacent to the holes in the vibrating structure.

These and other aspects and advantages of the invention are described inthe following description, claims and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a partial cutaway view of an exemplary apparatushaving an aerosol generator for aerosolizing liquids according to theinvention.

FIG. 2 is a schematic diagram of an inhalation flow sensor for detectingwhen a patient begins to inhale from an aerosolizing apparatus accordingto the invention.

FIG. 3 is a cross-sectional side view of an aerosol generator of theaerosolizing apparatus of FIG. 1.

FIGS. 4-9 illustrate cross-sectional side views of a container and apiston pump used in the apparatus of FIG. 1 to deliver a predeterminedvolume of liquid to the aerosol generator. The views illustrated inFIGS. 4-9 show various states of the piston pump when metering andtransferring liquids from the container to the aerosol generator.

FIG. 10 is a schematic view of an aerosolizing system having a removablecartridge holding a substance that is in a solid state according to theinvention.

FIG. 11 illustrates the aerosolizing system of FIG. 10 having thecartridge removed for cleaning of the aerosol generator according to theinvention.

FIG. 12 is a cross sectional side view of an alternative apparatus foraerosolizing a solution according to the invention.

FIG. 13 illustrates a dual chamber drug cartridge and an aerosolgenerator of the apparatus of FIG. 12.

FIGS. 14-17 illustrate the drug cartridge of FIG. 13 in various statesof operation to dispense a solution onto the aerosol generator accordingto the invention.

FIG. 18 illustrates the apparatus of FIG. 1 with an alternativecartridge to deliver liquids to the aerosol generator according to theinvention.

FIG. 19 illustrates the cartridge and aerosol generator of FIG. 18.

FIG. 20 is a cross-sectional view of the cartridge of FIG. 19.

FIG. 21 is a more detailed view of the cartridge of FIG. 19.

FIG. 22 is a cross-sectional side view of a dispensing system having adrug cartridge and a piston pump according to the invention.

FIG. 23 shows a chamber having a deformable wall in a collapsedcondition.

FIG. 24 shows the chamber of FIG. 23 expanded to hold fluid.

FIG. 25 shows another deformable wall for the chamber.

FIG. 26 shows the wall of FIG. 25 expanded to hold fluid.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

The invention provides exemplary systems, apparatus and methods forreconstituting a solid substance that is in a dry state with liquid,such as water, to form a solution and for transporting the solution toan aerosol generator for subsequent atomization. In one exemplaryembodiment, the system comprises a liquid dispenser, a cartridgecontaining the substance that is in the dry state, and an aerosolgenerator. In use, the cartridge is coupled to an outlet of thedispenser. The user then actuates the liquid dispenser so that liquid isdispensed from the dispenser and enters into the cartridge. As theliquid flows through the cartridge, the dry substance is dissolved intothe liquid and exits the cartridge as a solution. Preferably, thecartridge is replaced and disposed after each use. In a preferredembodiment, an outlet end of the cartridge is positioned near theaerosol generator so that the solution disposed on the aerosol generatoris readily available for atomization.

In one alternative, a two step process is employed to reconstitute thesolution and deliver the solution to the aerosol generator. First, aportion of a unit volume of liquid, such as one-half a unit volume, issupplied to the cartridge when the liquid dispenser is operated. Theuser then waits a predetermined amount of time, such as about 10seconds, and again operates the liquid dispenser to deliver sufficientliquid into the cartridge to force a unit volume of solution from thecartridge an onto the aerosol generator. In this way, a period of timeis provided to allow more of the substance to dissolve in the liquid.

In another aspect of the invention, exemplary systems and methods areprovided for metering relatively small volumes of liquid directly from acontainer and for delivering the metered volume to an atomizer. Thesystems and methods are configured to precisely meter and deliverrelatively small volumes of liquid, typically in the range from about 10μL to about 100 μL. When delivering volumes in the range from about 10μL to 50 μL, the invention preferably employs the use of a piston pumpthat is connected to a canister as described in greater detailhereinafter. For volumes in the range from about 50 μL to about 100 μL,a pharmaceutical pump is preferably employed, such as metered dose S4pump, commercially available from Somova S. p.A. Milano, Italy.Optionally, such pharmaceutical pumps may also contain a pharmaceuticalmedicament which may be delivered directly to the aerosol generator. Asone example, the pharmaceutical medicament may comprise a suspension ofcolica steroid for treatment of asthma.

Another feature of the liquid dispensers of the invention is that theyare configured to prevent or substantially reduce the possibility ofcontamination. In this way, each subsequent dosage delivered by theliquid dispenser is not contaminated when delivered to the atomizer.Referring now to FIG. 1, an exemplary apparatus 10 for atomizing aliquid will be described. Apparatus 10 comprises a housing 12 which isconfigured to hold the various components of apparatus 10. Housing 12 ispreferably constructed to be lightweight and pocket-sized, typicallybeing molded of a plastic material. Housing 12 is divided into twoseparable portions. A first portion 14 includes an electronicscompartment and a second portion 16 includes a liquid holdingcompartment for holding a canister 18, an aerosol generator 22, and amouthpiece 20 through which the atomized liquids are dispensed to thepatient. Conveniently, second portion can be separated from firstportion 14 by sliding a knob 23. Optionally, second portion 16 havingthe liquid holding component may be disposed following separation fromfirst portion 14. Second portion 16 may be disposed along with canister18, or canister 18 may be disposed separately.

Apparatus 10 further includes an inhalation flow sensor 24 which detectsthe inhalation flow produced by the patient when inhaling frommouthpiece 22. Upon detection of the inhalation, sensor 24 sends anelectrical signal to an electronic circuit (not shown) which in turnsends an alternating voltage to vibrate a piezoelectric member 26 ofaerosol generator 22 to aerosolize a liquid. Sensor 24 preferablycomprises a flexure foil and an electro-optical sensor. The flexiblefoil deflects in response to the inhalation airflow produced when apatient inhales from mouthpiece 20. The optical sensor is configured todetect deflection of the flexible foil so that a signal may be producedto vibrate piezoelectric member 26.

Referring now to FIG. 2, a schematic diagram of an inhalation flowsensor 24 will be described. Flow sensor 24 comprises a flexible foil 28having an extension 30. Inhalation flow sensor 24 further includes anoptical sensor 32 which includes a light emitting diode (LED) 34 and alight sensitive transistor 36 placed in apposition to LED 34 so that LED34 continuously transmits a light beam 38 to transistor 36. When thepatient inhales, the inhalation airflow causes flexible foil 28 todeflect and move extension 30 downward until it crosses light beam 38and causes an optical interruption that is detected by transistor 36.Transistor 36 then sends a signal to trigger activation of an aerosolgenerator to produce an aerosol.

By configuring inhalation flow sensor 24 in this manner, aerosolgenerator 22 is actuated only in response to the detection of aninhalation airflow produced by a patient. In this way, the patient maybe administered a single dose using either a single inhalation ormultiple inhalations. Preferably, inhalation flow sensor 24 is triggeredat an inhalation flow rate of at least 15 liters per minute. However, itwill be appreciated that sensor 24 may be constructed to trigger ateither lower or higher flow rates. Adjustment of the actuation point maybe accomplished by altering the flexible stiffness of foil 28, byselecting different materials for constructing foil 28 or by changingthe thickness of foil 28.

Alternatively, the inhalation flow sensor may be constructed from apiezoelectric film component. The piezoelectric film component producesan electrical signal when it deflects. The magnitude of the electricalsignal is proportional to the magnitude of deflection. In this way, theelectrical signal that is produced by the piezoelectric film componentcan be used to detect the magnitude of the inhalation flow. In thismanner, the output of the aerosol generator may be adjusted inproportion to the inhalation airflow. Such a proportional output fromthe aerosol generator is particularly advantageous in that it preventsthe coalescence of particles and controls the aerosol productionaccording to the inhalation flow. Control of the aerosol output may beadjusted by turning the aerosol generator on and off sequentially. Theratio between the on time and the off time, generally defined as theduty cycle, affects the net flow. An exemplary piezoelectric filmcomponent with such characteristics is commercially available from ATOAutochem Sensors, Inc., Valley Forge, Pa.

Referring back to FIG. 1, the electronic circuit (not shown) withinfirst portion 14 includes electrical components to detect the presenceof liquid on aerosol generator 22 and to send a signal to the userindicating that all of the liquid has been aerosolized. In this way, theuser will know if additional inhalations will be required in order toreceive the prescribed amount of medicament. The sensing circuitpreferably comprises a voltage sensing circuit (not shown) which detectsthe voltage across piezoelectric element member 26. Since the voltageacross piezoelectric member 26 is proportionally related to the amountof liquid in surface tension contact with an aperture plate 40 (see FIG.3) of aerosol generator 22, it can be determined, based on the voltage,whether any liquid is left remaining. For example, when aerosolizationis initiated, the voltage is high. At the end of aerosolization, thevoltage is low, thereby indicating that the aerosolization process isnear completion. Preferably, the sensing circuit is configured to betriggered when about 95% of the liquid has been aerosolized. Whentriggered, the sensing circuit turns on a light emitting diode (LED) 42indicating that the prescribed dosage has been delivered.

Referring now to FIG. 3, construction of aerosol generator 22 will bedescribed in greater detail. As previously described, aerosol generator22 includes a vibratable aperture plate 40 and annular piezoelectricmember 26. Aerosol generator 22 further comprises a cup-shaped member 44to which piezoelectric member 26 and aperture plate 40 are attached asshown. Cup-shaped member 44 includes a circular hole 46 over whichaperture plate 40 is disposed. Wires (not shown) connect piezoelectricmember 26 to the electrical circuitry within portion 14 (see FIG. 1)which in turn is employed to vibrate piezoelectric member 26.

Cup-shaped member 44 is preferably constructed of a low damping metal,such as aluminum. Aperture plate 40 is disposed over hole 46 such that arear surface 48 of aperture plate 40 is disposed to receive liquid fromcanister 18 (see FIG. 1). Although not shown, aperture plate 40 includesa plurality of tapered apertures which taper from rear surface 48 to afront surface 50. Exemplary aperture plates which may be used with theinvention include those described the '740 patent, the '550 patent, andthe '637 patent, previously incorporated by reference.

Aperture plate 40 is preferably constructed of a material that may beproduced by a metal electroforming process. As an example, apertureplate 40 may be electroformed from palladium or a palladium alloy, suchas palladium cobalt or palladium nickel. Aperture plate 40 may furtherbe gold electroplated to enhance its corrosion resistance.Alternatively, aperture plate 40 may be constructed of nickel, anickel-gold alloy, or a combination of nickel and nickel-gold alloyarranged such that the nickel-gold alloy covers the external surfaces ofthe aperture plate. The nickel-gold alloy may be formed using a goldelectroplating process followed by diffusion at an elevated temperatureas described generally in Van Den Belt, TGM, “The diffusion of platinumand gold in nickel measured by Rutherford Fact Scattering Spectrometry”,Thin Solid Film, 109 (1983), pp. 1-10. The complete disclosure of thisreference is incorporated herein by reference. A small amount ofmanganese may also be introduced to the nickel during the electroformingprocess so that the nickel can be heat treated at an elevatedtemperature as described generally in U.S. Pat. No. 4,108,740,incorporated herein by reference. The gold-nickel alloy is particularlyuseful in protecting the nickel components, and particularly theelectroformed nickel components, from corrosion caused by platingporosity. The diffusion process may be useful for other applicationswhich require corrosion protection for nickel components, andparticularly nickel electro formed components, such as, for example,inkjet aperture plates, other spray nozzle plates, and the like.

As another alternative, corrosion resistance of the aperture plate maybe enhanced by constructing the aperture plate of a composite electroformed structure having two layers, with the first electro formed layercomprising nickel and the second electro formed layer comprising gold.The thickness of the gold in the composite in preferably at least twomicrons, and more preferably, at least five microns. Alternatively, thesecond layer may be electro formed from palladium or anothercorrosive-resistant metal. The external surfaces of the aperture platemay also be coated with a material that prevents bacteria growth, suchas polymyxin or silver. Optionally, other coatings that enhancewetability may be applied to the aperture plate.

In one embodiment, the aperture plate is protected from corrosiveliquids by coating the aperture plate with agents that form a covalentbond with the solid surface via a chemical linking moiety. Such agentsare preferred because the are typically biocompatable with acidicpharmaceutical liquids. The agent may be photoreactive, i.e. activatedwhen subjected to light or may be activated when subjected to moistureor to any other means of energy. Further, the agent may have varioussurface properties, e.g. hydrophobic, hydrophilic, electricallyconductive or non-conductive. Still further, more than one agent may beformed on top of each other. Types of coatings that may be included onthe aperture plate are described in U.S. Pat. Nos. 4,979,959; 4,722,906;4,826,759; 4,973,493; 5,002,582; 5,073,484; 5,217,492; 5,258,041;5,263,992; 5,414,075; 5,512,329; 5,714,360; 5,512,474; 5,563,056;5,637,460; 5,654,460; 5,654,162; 5,707,818; 5,714,551; and 5,744,515.The complete disclosures of all these patents are herein incorporated byreference.

Cup-shaped member 44 is disposed within a housing 52 which preventsliquids from coming into contact with piezoelectric member 26 and withcup-shaped member 44. Cup-shaped member 44 is suspended within housing52 by two elastic rings 54 and 56. Ring 54 is positioned between housing52 and the circumference of cup-shaped member 44. Ring 56 is positionedbetween the inner diameter of piezoelectric member 26 and a shieldmember 58. Such an arrangement provides a hermetic seal that preventsthe contact of liquids with the piezoelectric member 26 withoutsuppressing the vibratory motion of cup-shaped member 44.

Referring back now to FIG. 1, aerosol generator 22 is axially alignedwith mouthpiece 20 so that when piezoelectric member 26 is vibrated,liquid droplets are ejected through mouthpiece 20 and are available forinhalation by the patient. As previously described, disposed withinsecond portion 16 is a canister 18 which holds the liquid medicament tobe atomized by aerosol generator 22. Canister 18 is integrally attachedto a mechanical pump 60 which is configured to dispense a unit volume ofliquid through a nozzle 62 to aerosol generator 22. Pump 60 is actuatedby pressing a knob 64 which pushes canister 18 downward to generate thepumping action as described in greater detail hereinafter. Pressing onknob 64 also puts pressure on an electrical microswitch 66 within secondportion 16. When actuated, microswitch 66 sends a signal to theelectrical circuit within first portion 14 causing a light emittingdiode (LED) (not shown) to blink indicating that apparatus 10 is readyfor use. When the patient begins to inhale, the inhalation is sensedcausing actuation of the aerosol generator.

As illustrated in FIG. 3, pump 60 delivers a unit volume of liquid 68(shown in phantom line) to rear surface 48 of aperture plate 40. Thedelivered volume 68 adheres to aperture plate 40 by solid/liquid surfaceinteraction and by surface tension forces until patient inhalation issensed. At that point, piezoelectric member 26 is actuated to ejectliquid droplets from front surface 50 where they are inhaled by thepatient. By providing the delivered volume 60 in a unit volume amount, aprecise dose of liquid medicament may be atomized and delivered to thelungs of the patient. Although canister 18 of FIG. 1 is shown as beingconfigured to directly deliver the dispensed liquid to the apertureplate, pump 60 may alternatively be configured to receive a cartridgecontaining a chemical in a dry state as described in greater detailhereinafter.

Referring now to FIGS. 4-10, a schematic representation of a canister138 and a piston pump 140 will be described to illustrate an exemplarymethod for dispensing a unit volume of a liquid medicament to anaperture plate, such as aperture plate 40 of apparatus 10 (see FIGS. 1and 3). Canister 138 comprises a housing 142 having an open end 144about which a cap 146 is placed. Disposed against open end 144 is awasher 148 which provides a seal to prevent liquids from escaping fromhousing 142. On top of washer 148 is a cylindrical member 150. Cap 146securely holds cylindrical member 150 and washer 148 to housing 142.Cylindrical member 150 includes a cylindrical opening 151 which allowsliquids to enter from canister 138. Cylindrical member 150 incombination with washer 148 also serve to securely position a holdingmember 152 about which a compression spring 154 is disposed.

Piston pump 140 comprises a piston member 156, cylindrical member 150, avalve seat 158 and compression spring 154. Piston member 156 has afrontal end 156A and a distal end 156B, with frontal end 156A providingthe piston action and distal end 156B providing the valve action.

Piston pump 140 is configured such that every time valve seat 158 isdepressed toward canister 138 and then released, a unit volume of liquidis dispensed through a tapered opening 161 in valve seat 158. Valve seat158 includes a valve seat shoulder 158A which is pressed to move valveseat inwardly, causing valve seat 158 to engage with distal end 156B toclose tapered opening 161.

As shown in FIG. 5, as piston member 156 is further depressed intocylindrical member 150, spring 154 is compressed and a metering chamber168 begins to form between frontal end 156A and cylindrical member 150.Frontal end 156A and distal end 156B are preferably constructed from asoft elastic material which provides a hermetic seal with cylindricalmember 150 and valve seat 158, respectively. Due to the seal betweenfrontal end 156A and cylindrical member 150, a vacuum is created withinmetering chamber 168 upon depression of piston member 156.

As piston member 156 is further moved into cylindrical member 150 (seeFIG. 6), spring 154 is further compressed and frontal end 156A movespast cylindrical opening 151 so that a gap is provided between frontalend 156A and cylindrical member 150. As frontal end 156A passes the edgeof cylindrical member 150, liquid from canister 138 is drawn intocylindrical member 150 by the vacuum that was created within meteringchamber 168. In FIG. 6, piston member 156 is in the filling position.

At the end of inward travel, the user releases the pressure on valveseat 158, allowing spring 154 to push piston member 156 back toward itsstarting position. As illustrated in FIG. 7, upon the return travel ofpiston member 156 to the starting position, frontal end 156A againengages cylindrical member 150 and forms a seal between the two surfacesto prevent any liquid within metering chamber 168 from flowing back intocanister 138.

Since the liquid within metering chamber 168 is generallyincompressible, as spring 154 pushes on piston member 156, the liquidwithin metering chamber 168 forces valve seat 158 to slide distally overpiston member 156. In so doing, the liquid within metering chamber 168is allowed to escape from the metering chamber through tapered opening161 of valve seat 158 as illustrated in FIG. 8.

As illustrated in FIGS. 7-9, liquid from metering chamber 168 isdispensed from tapered opening 161 as frontal end 156A travels length L.As frontal end 156A passes through length L, it is in contact withcylindrical member 150. In this way, the liquid within metering chamber168 is forced out of tapered opening 161 during this length of travel.After passing through Length L, frontal end 156A passes out of sealingrelationship with cylindrical member 150 so that no further liquid isdispensed from tapered opening 161. Hence, the amount of liquiddispensed is proportional to the diameter of cylindrical member 150 overlength L. As such, piston pump 140 may be designed to dispense a knownvolume of liquid each time piston member 156 travels from the startingposition to the filling position and then back to the starting position.Since piston member 156 must be fully depressed to the filling positionin order to create a gap between frontal end 156A and cylindrical member150, a way is provided to ensure that partial volumes can not bedispensed.

As shown in FIG. 9, valve seat 158 includes a shoulder 170 which engagesa stop 172 on cylindrical member 150 to stop distal movement of valveseat 158 relative to cylindrical member 150. At this point, piston pump140 is at an ending dispensing position which corresponds to thestarting position as initially illustrated in FIG. 4. In this position,spring 154 forces distal end 156B of piston member 156 into taperedopening 161 to provide a seal and prevent contaminants from enteringinto piston 140.

Valve seat 158 is preferably coated with a material that inhibitsproliferation of bacteria. Such coatings can include, for example,coatings having a positive electric charge, such as polymyxin,polyethylinimin, silver, or the like.

The invention further provides a convenient way to store chemicalsubstances in the solid or dry state and then to dissolve the chemicalsubstance with liquid from the canister to form a solution. In this way,chemical substances that are otherwise susceptible to degradation can bestored in the dry state so that the shelf life of the product isextended. An exemplary embodiment of a cartridge 180 for storing suchchemical substances that are in the dry state is illustrated in FIG. 10.For convenience of illustration, cartridge 180 will be described inconnection with piston pump 140 and canister 138, which in turn may becoupled to an aerosolization apparatus, such as apparatus 10, toaerosolize a medicament as previously described. Cartridge 180 comprisesa cylindrical container 182 having an inlet opening 184 and outletopening 186. Inlet opening 182 is sized to be coupled to piston pump 140as shown. Disposed within container 182 is a first filter 188 and asecond filter 190. Filter 188 is disposed near inlet opening 184 andsecond filter 190 is disposed near outlet opening 186. A chemicalsubstance 192 which is in a dry state is disposed between filters 188and 190. Chemical substance 192 is preferably held within a supportstructure to increase the rate in which the chemical substance isdissolved.

The support structure may be constructed of a variety of materials whichare provided to increase the rate in which the chemical substance isdissolved. For example, the support structure may comprise an open cellmaterial such as a polytetrafluoroethylene (PTFE) matrix materialcommercially available from Porex Technologies, Farburn, Ga. Preferably,such an open cell material has a pore size in the range from about 7 μmto about 500 μm, and more preferably about 250 μm. Alternatively,various other plastic materials may be used to construct the open cellmatrix, including olyethylene (HDPE), ultra-high molecular weightpolyethylene (UHMW), polypropylene (PP), polyvinylidene fluoride (PVDF),nylon 6 (N6), polyethersulfone (PES), ethyl vinyl acetate (EVA), and thelike. Alternatively, the support structure may be constructed of a wovensynthetic material, a metal screen, a stack of solid glass or plasticbeads, and the like.

An exemplary method for placing chemical substance 192 into container182 is by filling container 182 with the chemical substance while thechemical substance is in a liquid state and then lyophilizing thesubstance to a dry state while the substance within the cartridge. Inthis way, filling of cartridge 180 with a chemical substance may beprecisely and repeatedly controlled. However, it will be appreciatedthat the chemical substance may be placed into cartridge 180 when in thesolid state.

Lyophilization is one exemplary process because it will tend to reducethe rate of various physical and chemical degradation pathways. If thesubstance comprises a protein or peptide, both the lyophilization cycle(and resulting moisture content) and product formulation can beoptimized during product development to stabilize the protein beforefreezing, drying and for long term storage. See Freeze Drying ofProteins, M. J. Pikal, BioPharm. 3, 18-26 (1990); Moisture InducedAggregation of Lyophilized Proteins in the Solid State, W. R. Liu, R.Langer, A. M. Klibanov, Biotech. Bioeng. 37, 177-184 (1991); FreezeDrying of Proteins. II, M. J. Pikal, BioPharm. 3, 26-30 (1990);Dehydration Induced Conformational Transitions in Proteins and TheirInhibition by Stabilizers, S. J. Prestrelski, N. Tedeschi, S. Arakawa,and J. F. Carpenter, Biophys. J. 65, 661-671 (1993); and Separation ofFreezing and Drying Induced Denaturation of Lyophilized Proteins UsingStress-Specific Stabilization, J. F. Carpenter, S. J. Prestrelski, andT. Arakawa, Arch. Biochem. Biphys. 303, 456-464 (1993), the completedisclosures of which are herein incorporated by reference. Adjustment ofthe formulation pH and/or addition of a wide variety of additivesincluding sugars, polysaccharides, polyoles, amino-acids, methylamines,certain salts, as well as other additives, have been shown to stabilizeprotein towards lyophilization.

As an example, which is not meant to be limiting, a cartridge was packedwith small glass beads having a diameter of approximately 0.5 mm. Thecartridge was filed with a solution of lysozyme at a concentration of 10mg/ml. To enhance its stability, the solution was combined with a formof sugar and with a buffer solution. The buffer solution was sodiumcitrate, and the sugar was mannitol. A twin 20 surfactant was also addedto the solution. The solution was then lyophilized in the cartridge.

The lyophilized substance may optionally contain a solubility enhancer,such as a surfactant as described in Journal of Pharmaceutical ScienceTechnology which is J.Pharmsei. Technology, 48; 30-37 (1994) thedisclosure of which is herein incorporated by reference. To assist inprotecting the chemical substance from destructive reactions while inthe dry state, various sugars may be added as described in Crowe, etal., “Stabilization of Dry Phospholipid Bilayer and Proteins by Sugars”,Bichem. J. 242: 1-10 (1987), and Carpenter, et al. “Stabilization ofPhosphofructokinase with Sugars Drying Freeze-Drying”, Biochemica. etBiophysica Acta 923: 109-115 (1987), the disclosures of which are hereinincorporated by reference.

In use, cartridge 180 is coupled to piston pump 140 and piston pump 140is operated as previously described to dispense a known volume of liquidinto cartridge 180. The supplied liquid flows through chemical substance192 and chemical substance 192 dissolves into the liquid and flows outof outlet opening 186 as a liquid solution 194. Outlet opening 186 isspaced apart from an aperture plate 196 of an aerosol generator 198 sothat liquid solution 198 will be deposited on aperture plate 196 asshown. Aerosol generator 198 further includes a cup shaped number 200and a piezoelectric member 202 and operates in a manner similar to theaerosol generator 22 as previously described. Hence, when aerosolgenerator 198 is operated, liquid solution 194 is ejected from apertureplate 196 in droplet form as shown.

One important feature of the invention is that cartridge 180 isremovable from piston pump 140 so that cartridge 180 may be discardedfollowing each use. As illustrated in FIG. 11, after cartridge 180 hasbeen removed, the user may optionally actuate piston pump 140 to againdeliver a volume of liquid 204 directly to aperture plate 96. Aerosolgenerator 198 is then operated so that, similar to an ultrasoniccleaner, the vibratory action removes any residual solution fromaperture plate 196. Liquids that may be held within canister 138 to formthe solution and to clean aperture plate 196 include sterile water, amixture of water with ethanol or other disinfectant, and the like.

In summary, the invention provides a portable aerosolizing apparatusthat is able to store a chemical substance in the dry state, and toreconstitute the chemical substance with liquid to form a solution justprior to administration. The invention further provides techniques foraerosolizing the solution and for cleaning the aerosol generator. Also,it will be appreciated that the aerosolization apparatus as describedherein may be used to aerosolize a liquid medicament that is not storedwithin a cartridge so that the liquid medicament is passed directly fromthe piston pump and on to the aperture plate for aerosolization.

Apparatus 10 may optionally be configured to warn the user when cleaningis needed. Such a feature is best accomplished by providing a processorwithin second portion 14 which is programmed to include an expectedamount of time required to aerosolize a dose received from canister 18.If the expected amount of time exceeded before the entire dose isaerosolized, it may be assumed that the apertures in the aperture plateare clogged, thereby requiring cleaning to clear the apertures. In suchan event, the processor sends a signal to an LED on apparatus 10indicating that cleaning is needed.

To determine whether all of the liquid has been aerosolized in theexpected time period, the processor records the amount of time that theaerosol generator is actuated. When the aerosol generator has beenactuated for the expected time, the voltage sensing circuit is actuatedto detect whether any liquid remains on the aperture plate as previouslydescribed.

Referring now to FIG. 12, an alternative embodiment of an apparatus 300for atomizing a liquid solution will be described. Apparatus 300includes a housing 302 that is divided into two separable portionssimilar to the embodiment of FIG. 1. A first portion 304 includesvarious electronics and a second portion 306 includes a liquid holdingcompartment. An aerosol generator 308 which is similar to aerosolgenerator 22 of FIG. 1 is disposed in second portion 306 to aerosolize asolution where it will be available for inhalation through a mouthpiece310. Conveniently, aerosol generator 308 includes a lip 312 to catch thesolution and maintain it in contact with the aerosol generator 308 untilaerosolized. Disposed above aerosol generator 308 is a drug cartridge314. As will be described in greater detail hereinafter, cartridge 314is employed to produce a solution which is delivered to aerosolgenerator 308 for aerosolization.

Coupled to cartridge 314 is a lead screw 316. In turn, lead screw 316 iscoupled to a micro-coreless DC motor 318. When motor 318 is actuated, itcauses a shaft 320 to rotate. This rotational motion is converted tolinear motion by lead screw 316 to translate a piston 322 withincartridge 314 as described in greater detail hereinafter. Motor 318 isactuated by appropriate electronics held in first portion 304. Further,a power source, such as a battery, is also held within first portion 304to supply power to motor 318. Aerosol generator 38 is operated in amanner essentially identical to that previously described in connectionwith the apparatus of FIG. 1.

Referring now to FIG. 13, construction of cartridge 314 will bedescribed in greater detail. Piston 322 includes a docking knob 324which mates with a connector 326 of lead screw 316. Docking knob 324 andconnector 326 are configured to facilitate easy coupling and uncoupling.Typically, motor 318 and lead screw 316 are securely coupled to housing308 (see FIG. 12), while cartridge 314 is configured to be removablefrom housing 302. In this way, each time a new drug cartridge isrequired, it may be easily inserted into apparatus 300 and coupled withlead screw 316.

Lead screw 316 is configured such that when motor 318 causes shaft 320to rotate in a clockwise direction, lead screw 316 is moved downward.Alternatively, when motor 318 is reversed, lead screw 316 is movedupward. In this way, piston 322 may be translated back and forth withincartridge 314. Motor 318 is preferably calibrated such that piston 322can be moved to selected positions within cartridge 314 as described ingreater detail hereinafter.

Cartridge 314 includes a first chamber 328 and a second chamber 330.Although not shown for convenience of illustration, first chamber 328 isfilled with a liquid and second chamber 330 includes a substance that isin a dry state. Such a substance preferably comprises a lyophilizeddrug, although other substances may be employed similar to theembodiment of FIG. 1. Separating first chamber 328 and second chamber330 is a divider 332. As shown in FIG. 13, divider 332 is in a homeposition which forms a seal between divider 332 and cartridge 314 sothat the liquid is maintained within first chamber 328 until divider 332is moved from its home position as described hereinafter.

Cartridge 314 includes an exit opening 333 which is disposed in closeproximity to aerosol generator 308. Once the solution is formed withincartridge 314, it is dispensed through exit opening 333 and on toaerosol generator 308 where it will be aerosolized for delivery to thepatient. Disposed across exit opening 333 is a filter 334 which servesto prevent larger drug particles from being flushed out onto aerosolgenerator 308, thus causing potential clogging of the apertures withinaerosol generator 308.

Referring now to FIGS. 14-17, operation of cartridge 314 to produce asolution which is delivered to aerosol generator 308 will be described.Cartridge 314 is constructed in a manner similar to the drug cartridgedescribed in U.S. Pat. No. 4,226,236, the complete disclosure of whichis herein incorporated by reference. As shown in FIG. 14, cartridge 314is in the home position where divider 332 maintains the liquid withinfirst chamber 328. When in the home position, cartridge 314 may beinserted into apparatus 300 and coupled to lead screw 316 (see FIG. 13).When ready to deliver an aerosolized solution to a patient, motor 318(see FIG. 13) is actuated to cause lead screw 316 to translate piston322 within cartridge 314 as illustrated in FIG. 15. As piston 322 istranslated within cartridge 314, it begins to move through first chamber328. Since the liquid is generally incompressible, the liquid will forcedivider 332 to move in the direction of second chamber 330. Formed inthe walls of cartridge 314 are one or more grooves 336 which are placedin communication with first chamber 328 as divider 332 moves away fromits home position. As such, the liquid within first chamber 328 isforced into chamber 330 as illustrated by the arrows. Once the liquid isable to flow around divider 332, the pressure acting against it isrelieved so that it remains in the position generally shown in FIG. 15.As the liquid enters into second chamber 330, the lyophilized drug isdissolved into the liquid to form a solution.

As illustrated in FIG. 16, piston 322 is translated until it engagesdivider 332. At this point, all of the liquid has been transferred fromfirst chamber 328 into second chamber 330. At this point, it mayoptionally be desired to mix the solution that has just been formedwithin second chamber 330. This may be accomplished by translatingpiston 322 backward toward the position illustrated in FIG. 15. In sodoing, a vacuum is created within first chamber 328 to draw the solutionfrom second chamber 330 into first chamber 328. As the solution flowsthrough grooves 336, the solution is agitated, causing mixing. Piston322 may then be translated back to the position shown in FIG. 16 to movethe liquid back into second chamber 330. This process may be repeated asmany times as needed until sufficient mixing has occurred.

After proper mixing, the solution is ready to be dispensed onto theaerosol generator. To do so, piston 332 is moved through second chamber330 as illustrated in FIG. 17. In turn, divider 332 is pushed againstfilter 334 to completely close second chamber 330 and force all of theliquid out exit opening 333.

One particular advantage of cartridge 314 is that a precise volume ofdrug is dispensed onto aerosol generator 308 to ensure that the patientwill receive the proper dosage. Further, by maintaining the drug in thedry state, the shelf life may be increased as previously described.

Following dispensing of the solution, cartridge 314 may be removed andreplaced with another replacement drug cartridge. Optionally, a cleaningcartridge may be inserted into apparatus 300 which includes a cleaningsolution. This cleaning solution is dispensed onto aerosol generator 308upon operation of motor 318. Aerosol generator 308 may then be operatedto clean its apertures using the cleaning solution.

Referring now to FIG. 18, an alternative apparatus 400 for atomizing aliquid will be described. Apparatus 400 is essentially identical toapparatus 10 except that canister 18 has been replaced with a continuousfeed cartridge 402. Cartridge 402 is configured to continuously feedliquid to aerosol generator 22 on demand so that enough liquid willalways be available each time aerosol generator 22 is actuated.Cartridge 402 also ensures that excessive liquid will not be supplied,i.e. it will supply only as much liquid as is atomized. Cartridge 402 isconstructed similar to the cartridges described in co-pending U.S.patent application Ser. No. 08/471,311, filed Apr. 5, 1995, the completedisclosure of which is herein incorporated by reference.

As illustrated in FIGS. 19-21, cartridge 402 comprises a liquidreservoir 404 and a face 406 which is adjacent the aperture plate ofaerosol generator 22 to supply liquid from liquid reservoir 404 to theaperture plate. A capillary pathway 408 extends between reservoir 404and face 406 to supply liquid to face 406 by capillary action. In orderto overcome the vacuum that is produced in reservoir 404, a ventingchannel 410 is in communication with pathway 408. In this way, air isable to enter into reservoir 404 to reduce the vacuum and allowadditional liquid to be transferred from reservoir 404.

In another embodiment, a drug cartridge may be coupled to a piston pumpto form a dispensing system that is used to supply a formation to anaerosol generator. For example, as shown in FIG. 22, a dispensing system430 comprises a cartridge 432 and a piston pump 434. Cartridge 432 ispatterned after cartridge 314 of FIG. 14 and includes a first chamber436 and a second chamber 438. Disposed in chamber 436 is a liquid (notshown) and disposed in second chamber 438 is a dried substance 440. Adivider 442 separates the chambers. In use, a plunger 444 is movedthrough chamber 436 to force divider 442 forward and to allow the liquidto enter chamber 438 and form a solution.

Piston pump 434 may be constructed similar to pump 138 of FIG. 4. Pump434 is operated to dispense a volume of the solution from chamber 438.Pump 434 may be disposed near an aerosol generator so that a volume ofthe solution will be available for atomization. In this way, knownvolumes of a solution that was formed from a direct substance may beprovided in an easy and convenient manner.

Referring to FIGS. 23 and 24, another aspect of the invention is shownwherein the same or similar reference numbers refer to the same orsimilar structure. A container 500 delivers fluid to a chamber 502. Thecontainer 500 and chamber 502 are contained within the housing 12(FIG. 1) and the aspects of the devices described above are equallyapplicable here. Fluid from the container 500 fills the chamber 502 atleast three times and more preferably at least twenty five times.

The chamber 502 is movable between the expanded position of FIG. 24 tothe collapsed position of FIG. 23. The chamber 502 expands as fluid isdelivered to the chamber 502 from the container 500 and collapses asfluid is expelled through holes 504 in a vibrating structure 506 duringoperation. The holes 504, which are exaggerated for clarity, arepreferably shaped and sized in the manner described herein. Thevibrating structure 506 is formed by the cup shaped member 44 and anelement 508 having the holes 504. The element 508 has a domed shape butmay be flat, curved or shaped in any other suitable manner. Thevibrating structure 506 preferably vibrates at a frequency of 80-190kHz, more preferably about 120-150 kHz, but may also operate at otherfrequencies. The vibrating structure 506 is vibrated with any suitabledevice and is preferably vibrated with the piezoelectric member 26.

The chamber 502 has a deformable wall 510 which deforms to containvarying amounts of fluid. The wall 510 preferably bows outward and awayfrom the vibrating structure 506 when the chamber 502 expands (FIG. 24).The chamber 502 is also bounded by a back side 503 of the element 508 sothat fluid in the chamber 502 is in contact with the vibrating structure506. The chamber 502 preferably contains a volume of 10-1000 μL, morepreferably 10-750 μL and most preferably about 10-500 μL when fullyexpanded. The wall 510 may be somewhat elastic, however, the wall 510 ispreferably flexible enough that the fluid pressure in the chamber 502 isno more than 15 psi, more preferably no more than 10 psi, and mostpreferably no more than 5 psi when the chamber 502 is full. Fluidtension developed at the holes 504 in the vibrating structure hold thefluid within the chamber 502.

The container 500 has a piston 512 movable within a cylinder 514containing the fluid. The piston 512 moves within the cylinder 514 todeliver a known quantity of fluid to the chamber 502. The piston 512 maybe manually actuated or moved with a motor-driven actuator. Thecontainer 500 may, of course, be any other suitable device or container500 including any other device described herein, without departing fromthe scope of the invention. Thus, the container 500 may have a number ofcompartments containing different substances and may have the valvesdescribed above.

A cap 516 is mounted to the container 500. The cap 516 has a needle 518which pierces a septum 520 on the container 500. The cap 516 ispreferably attached to the container 500 immediately before use so thatthe septum 520 is not pierced until just before the container 500 ismounted within the housing 12. The container 500 is then mounted to aholding element 522 with a threaded connection 524. The holding element522 is mounted within the housing 22 in any suitable manner. The needle518 defines a fluid path 526 between the container 500 and the chamber502.

A valve 528 maintains sterility in the container 500 and prevents fluidflow from the chamber 502 to the container 500. The valve 528 ispreferably a slit-type valve 530 but may, of course, have any othersuitable structure. The valve 528 has upper and lower lips 532, 534which connect the valve 528 to the wall 510. The valve 528 may also havea threaded connection with the wall 510 which engages the wall 510 asthe container 500 engages the holding element 522.

Use of the device is now described. The cap 516 is attached to thecontainer 500 so that the needle 518 pierces the septum 520.Alternatively, the cap 516 may be already attached to the container 500with the valve 528 maintaining sterility of the container 500 beforeuse. The cap 516 is then rotated into engagement with the holdingelement 522 which causes the valve 528 to engage and the wall 510. Theuser then selects a desired amount of fluid to be delivered to thechamber 502. The piston 512 is then moved an appropriate distance todeliver the desired amount of fluid. As fluid is delivered from thecontainer 500, the valve 528 opens and the chamber 502 expands toaccommodate the fluid. The chamber 502 may be completely or partiallyfilled. As the chamber 502 is filled, the fluid pressure preferablyremains within the ranges described above. The piezoelectric member 26is then used to induce vibrations in the vibrating structure 506.Vibration of the vibrating structure 506 forces fluid from the chamber502 through the holes 504 and out front side 507 of the vibratingstructure 506.

Referring to FIGS. 25 and 26, another aspect of the invention is shownwherein the same or similar reference numbers refer to the same orsimilar structure. The dimensions, operation and use described above,such as in connection with FIGS. 23 and 24, are equally applicable here.The container 500 and chamber 502 operate similar to the container 500and chamber 502 described above in that the container 500 delivers fluidto the chamber 502. The chamber 502 is partially defined by the backside 503 of the vibrating structure 506 and a deformable wall 510A.

The container 500 differs from the container 500 in that wall 510A maybe replaced periodically and, in the preferred embodiment, is replacedwith each new container 500. A cap 516A has the needle 518 forpenetrating the septum 520 on the container 500 as described above. Thecap 516A, needle 518, and wall 510A may be mounted to the container 500immediately before mounting the container 500 to the holding element522. Alternatively, the wall 510A, needle 518, cap 516A and container500 may be packaged together. A valve 530, preferably a slit-type valve532, is formed at the end of the needle 518 to isolate the chamber 502from the container 500. The valve 530 defines a fluid outlet 534positioned less than 1 mm and more preferably less than 0.5 mm from theback side 503 of the vibrating structure 506. The valve 530 ispreferably positioned adjacent the holes 504 in the vibrating structure506.

A spring 534 holds the wall 510A against the vibrating structure 506 toseal the chamber 502. The spring 534 is compressed as the container 500is advanced into engagement with the holding element 522. The spring 534is embedded in the wall 510A and in the cap 516A. The wall 510A ispreferably made of a material that has a low bending stiffness whichproduces little resistance when expanding. In this manner, the pressurein the chamber may still be less than 15 psi and more preferably lessthan 10 psi as mentioned above. The fluid pressures are maintained atthe fluid volumes mentioned above.

The wall 510A has a portion 536 which conforms to the shape of the backside 503 of the vibrating structure 522 when collapsed so that the fluidcan be substantially, and preferably completely, removed from thechamber 502. In this manner, the volume remaining in the chamber 502 isless than 10 μL, more preferably less than 5 μL and most preferably lessthan 2 μL. The portion 536 of the wall 510A conforming to the vibratingstructure 522 is preferably adjacent the holes 504 in the vibratingstructure 506.

In another aspect of the invention, the vibrating structure 506 is ableto drop the pressure in the chamber 502 below atmospheric pressure tohelp collapse the wall 510, 510A. When the vibrating structure 522 isvibrated, fluid can be forced through the holes 504 when pressure in thechamber 502 is below atmospheric pressure. The device shown in FIGS.25-26 is used in the same manner as the device of FIGS. 23-24 and thediscussion above is incorporated here.

The invention has now been described in detail, however, it willappreciated that certain changes and modifications may be made. Forexample, although illustrated in the context of delivering liquid to anaperture plate, the apparatus and methods may be employed to deliverknown quantities of liquid to other types of atomization devices.Therefore, the scope and content of this invention are not limited bythe foregoing description. Rather the scope and content are to bedefined by the following claims.

What is claimed is:
 1. A device for aerosolizing a liquid, comprising: ahousing; a vibrating structure having a front side, a back side and aplurality of holes extending between the front and back sides, thevibrating structure being mounted within the housing; means forvibrating the vibrating structure; a chamber containing a liquid andhaving a deformable wall movable between a collapsed position and anexpanded position, wherein the deformable wall is movable to thecollapsed position to expel substantially all of the liquid from thechamber for delivery through the plurality of holes in the vibratingstructure upon vibration with the vibrating means.
 2. The device ofclaim 1, wherein: the chamber contains a volume of less than 10 uL whenin the collapsed condition.
 3. The device of claim 1, wherein: thevibrating means is a piezoelectric element coupled to the vibratingstructure.
 4. The device of claim 1, wherein: the chamber contains thefluid at a fluid pressure of less than 15 psi when in the expandedposition.
 5. The device of claim 1, wherein: the chamber contains thefluid at a fluid pressure of less than 5 psi when in the expandedposition.
 6. The device of claim 1, wherein: the vibrating structurevibrates at a frequency of 120-150 kHz.
 7. A method of aerosolizing aliquid, comprising the steps of: providing a device for aerosolizing aliquid, the device having a housing, a vibrating structure, and achamber, the vibrating structure having a plurality of holes thereinextending between a front side and a back side, the chamber containing aliquid and being at least partially defined by a wall; squeezing thechamber to collapse the wall, thereby delivering a desired quantity offluid to the vibrating structure; and vibrating the vibrating structureto expel substantially all of the liquid delivered from the chamber. 8.The method of claim 7, wherein: the delivering step is carried out witha fluid pressure of less than 15 psi in the chamber.
 9. The method ofclaim 7, further comprising the step of: removing and replacing thewall.
 10. The method of claim 7, wherein: the providing step is carriedout with the wall having a portion which generally conforms to a shapeof the back side of the vibrating structure when in the collapsedposition.
 11. The method of claim 7, wherein: the providing step iscarried out with the wall mounted to the vibrating structure.
 12. Themethod of claim 7, wherein: the vibrating step is carried out with thepressure in the chamber being less than a pressure at the front side ofthe vibrating structure.